JP2021536481A - How to prepare lenvatinib - Google Patents

Abstract

The present invention relates to a method for preparing lenvatinib of formula (I) from 4-amino-3-chloro-phenol and 4-chloro-7-methoxyquinoline-6-carboxamide. [Chemical 1] [Selection diagram] None

Description

The present invention relates to a method for preparing lenvatinib of formula (I) from 4-amino-3-chloro-phenol and 4-chloro-7-methoxyquinoline-6-carboxamide.

Lenvatinib of formula (I), first disclosed in WO 0232872, is used as a mesylate salt for the treatment of differentiated thyroid cancer that is not treated with radioactive iodine. Lenvatinib (I) is also active against advanced renal cell carcinoma.

US Pat. No. 7,683,172 discloses a method for preparing lenvatinib (I) from 4-amino-3-chloro-phenol and 4-chloro-7-methoxyquinoline-6-carboxamide:
(1) Conversion of 4-amino-3-chloro-phenol (II) to the corresponding phenylcarbamate derivative (III);

(2) The compound of formula (V) is obtained by the reaction of the derivative (III) obtained in step (1) with cyclopropylamine;

(3) Lenvatinib (I) is obtained by a coupling reaction between compound (V) obtained in step (2) and 4-chloro-7-methoxyquinoline-6-carboxamide of formula (VI);

(4) Crystallization of lenvatinib (I).

The main drawbacks of this method are 1 equivalent of 4-chloro-7-methoxyquinoline-6-carboxamide (VI), 1.2 equivalents of the urea derivative (V) obtained in step (2), and 2 equivalents of carbonate. In step (3), which is carried out by mixing cesium, or 1.2 equivalents of sodium t-butoxide, in a dimethyl sulfoxide solution at 65-70 ° C. for 23 hours. At the end of the reaction, the product is isolated by crystallization. Under these conditions, the precipitate was found to be contaminated with 1.8% impurities (VII), 0.5% impurities (VIII) and 1.7% impurities (IX). Impurities (VIII) and (IX) are described in CN 107266363. The large amount of the impurities requires an impractical number of crystallizations that adversely affect the process yield. Therefore, there is still a need for an improved method of preparing lenvatinib (I) that overcomes the above drawbacks.

In the coupling step between 4-chloro-7-methoxyquinoline-6-carboxamide (VI) and the intermediate of formula (V), by selecting a narrow range of equivalent reactants and temperatures, the above drawbacks Was found to be able to overcome.

Therefore, the present invention relates to a method for preparing lenvatinib of the formula (I).

(a) 1 equivalent of 4-chloro-7-methoxyquinoline-6-carboxamide (VI) and 2 equivalents of compound of formula (V) at a temperature in the range 45-55 ° C, preferably 50 ° C for dimethyl sulfoxide (DMSO). In the process of reacting in the presence of cesium carbonate to obtain lenvatinib (I); and

(b) 1: 3 DMSO: Crystallization of compound (I) in dichloromethane (DCM);
including.

The step (a) is preferably carried out at 50 ° C., preferably for 24 hours, in the presence of 2 equivalents of cesium carbonate as a base in dimethyl sulfoxide. The lower reaction temperature and the increased amount of urea derivative (V) make it possible to reduce the formation of impurities during the reaction and thus the content of impurities in the final precipitate. In fact, compound (VII) decreased from 1.8% to 0.08%, compound (VIII) decreased from 0.5% to 0.15%, and compound (IX) decreased from 1.7% to 0.11%. did. The low levels of impurities at this stage were lenvatinib (I) with HPLC purity = 99.6% after recrystallization in 1: 3 DMSO: DCM and the corresponding mesylate salt with all impurities less than 0.10%. Made it possible to get.

Compound (V) was obtained by reaction of 4-amino-3-chloro-phenol (II) with phenylchloroformate to give phenylcarbamate (III), followed by the following as disclosed in US 7683172: React with cyclopropylamine (IV) according to the scheme:

According to a preferred embodiment, the first two steps of the process described in US Pat. No. 7,863,172 are combined in a single step.

Specifically, 4-amino-3-chlorophenol is first converted to phenyl (III) carbamate by reaction with phenyl chloroformate in 2-methyltetrahydrofuran and a saturated sodium bicarbonate solution. When the starting material is consumed, the aqueous phase is separated from the organic phase containing compound (III). Cyclopropylamine (IV) is added directly to the organic phase and the mixture is stirred at 50 ° C. for 3 hours. At the end of the reaction, excess cyclopropylamine (IV) is removed by acid washing. Final crystallization in 4: 1 ethyl acetate: heptane allows removal of phenol, resulting in product (V) as white crystals with HPLC purity ≥99.7% and 90% yield.

The following examples describe the invention in more detail.

Example 1 1- (2-Chloro-4-hydroxyphenyl) -3-cyclopropylurea (V)
4-Amino-3-chloro-phenol hydrochloride (II) (60.0 g, 333.3 mmol, 1 eq) was suspended in 2-methyltetrahydrofuran (180 mL, 3 V) and the suspension cooled at 0-5 ° C. did. An aqueous solution (650 ml) of NaHCO ₃ (58.8 g, 699.9 mmol, 2.1 eq) was added dropwise over 25 minutes and maintained below 10 ° C. A solution of phenylchloroformate (57.4 g, 46.0 mL, 366.7 mmol, 1.1 eq) in 2-methyltetrahydrofuran (96 mL) was added dropwise over 25 minutes while keeping the temperature below 10 ° C. The mixture was stirred at 0-5 ° C. for 10 minutes. Reactions were monitored by quantitative TLC (95: 5 DCM: MeOH; UV254 nm) until 4-amino-3-chlorophenol was less than 1%.

The phase was separated and removed and cyclopropylamine (IV) (37.9 g, 46.0 mL, 666.6 mmol, 2 eq) was added dropwise to the organic phase over 30 minutes to maintain the temperature below 10 ° C. The mixture was stirred at 50 ° C. for 3 hours. The reaction process was monitored by quantitative TLC (7: 3 hexane: EtOAc, UV 254 nm) until the phenylcarbamate intermediate (III) was less than 0.5%.

The reaction mixture was cooled to room temperature and 1 MH ₂ SO ₄ (200 ml) was added in 15 minutes. The aqueous phase was removed and the organic phase was diluted with 2-methyltetrahydrofuran (60 mL, 1V), and washed with 10% sodium chloride (200 mL) and H ₂ O (50mL). The organic phase _{was concentrated to 120 ml (2 V) at T ext} = 50 ° C. and P = 150 mbar. Ethyl acetate (240 mL, 4 V) was added and the resulting mixture was concentrated to 240 mL (4 V). Ethyl acetate (120 mL, 2 V) was added and the mixture was concentrated to 240 mL (4 V). The latter operation was repeated twice. The obtained slurry was stirred at room temperature for 1 hour, and n-heptane (60 mL, 1 V) was added. After 30 minutes, the precipitate was filtered and washed with 4: 1 EtOAc: n-heptane (60 mL, 1 V) and n-heptane (60 mL, 1 V). The white solid was dried under vacuum at 55 ° C. for 16 hours to give 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropylurea (V) (68.5 g, y = 91%). Typical HPLC purity was 99.74-99.93%.

^{1 1} H-NMR (400MHz, DMSO-d ₆ ) δ (ppm): 0.38 (2H, m), 0.61 (2H, m), 2.50 (1H, m,), 6.65 (1H) , dd, J = 8.9 Hz, J = 2.8 Hz,), 6.77 (1H, d, J = 2.8 Hz), 6.79 (1H, d, J = 2.6 Hz), 7. 53 (1H, s), 7.68 (1H, d, J = 8.9Hz), 9.44 (1H, s).
Comparative Example 2 4- (3-Chloro-4- (cyclopropylaminocarbonyl) -aminophenoxy) -7-methoxy-6-quinoline carboxamide (I) (coupling conditions according to Example 3 of US 7683172)
4-Chloro-7-methoxyquinoline-6-carboxamide (VI) (0.983 g, 4.15 mmol, 1 equivalent) and 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropylurea (V) ( 1.13 g, 4.99 mmol, 1.2 eq) was suspended in 20 mL DMSO. Cesium carbonate (2.71 g, 8.32 mmol, 2 eq) was added and the mixture was stirred at 70 ° C. for 23 hours. The reaction mixture was cooled to room temperature and water (50 mL) was added to precipitate the product. The precipitated crystals were filtered and dried to give a dark blue solid (1.58 g, 3.70 mmol, y = 89%, impurity content reported in Table 1). Crude lenvatinib (1.58 g, 3.70 mmol) was dissolved in DMSO (7.8 mL, 5 V) at 70 ° C. The solution was cooled to room temperature and dichloromethane (23.7 mL, 15 V) was added in 15 minutes. The mixture was stirred at room temperature for 16 hours and at 0-5 ° C. for 1 hour. The suspension was filtered and the solid was washed with 1: 3 DMSO: DCM (3.1 mL, 2 V) and ground 3 times with pure DCM (6.2 mL, 4 V). The solid was dried under vacuum at 60 ° C. for 24 hours to give lenvatinib (I) (34.07 g, 79.81 mmol, crystallization yield = 79%, total yield = 67%). A typical A% HPLC purity is 99.6%.

(1.09 g, 2.55 mmol, crystallization yield = 69%, total yield = 62%. Typical A% HPLC purity is 95.0%, impurity content is reported in Table 1.

^{1 1} H-NMR (400 MHz, DMSO-d6) δ (ppm): 0.43 (2H, m), 0.65 (2H, m), 2.57 (1H, m), 4.08 (3H, s) ), 6.46 (1H, d, J = 6.6Hz), 7.18 (1H, brs), 7.25 (1H, dd, J = 2.8Hz, J = 9.1Hz), 7.48 (1H, d, J = 2.8Hz), 7.52 (1H, s), 7.70 (1H, s), 7.83 (1H, s), 7.96 (1H, s), 8. 25 (1H, d, J = 9.1Hz), 8.63 (2H, m).

Example 3 4- (3-Chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinoline carboxamide (I)
4-Chloro-7-methoxyquinoline-6-carboxamide (VI) (32.0 g, 135.2 mmol, 1 equivalent) and 1- (2-chloro-4-hydroxyphenyl) -3-cyclopropylurea (V) ( 61.30 g, 270.4 mmol, 2 eq) was suspended in DMSO (192 mL, 6 V) under nitrogen. Cesium carbonate (88.11 g, 270.4 mmol, 2 eq was added and the mixture was stirred at 50 ° C. for 24 hours under a nitrogen atmosphere. The reaction mixture was cooled to room temperature and water (192 mL, 6 V) was added dropwise over 40 minutes. in addition, the product was precipitated resulting suspension was filtered off crystals of 1 hour stirring the precipitate at room temperature, 1:.. 1 DMSO: washed with _{H 2 O (64mL, 2V)} , water Grinded 3 times at (130 mL, 4 V). The solid was dried under vacuum at 60 ° C. for 18 hours to a light brown / gray solid (53.25 g, 124.7 mmol, y = 85%, impurities reported in Table 1). Content) was obtained. Crude lembatinib (53.25 g, 124.7 mmol) was dissolved in DMSO (450 mL, 5 V) at 70 ° C., the solution was cooled to room temperature and dichloromethane (1350 mL, 15 V) was added in 15 minutes. The mixture was stirred at room temperature for 16 hours at 0-5 ° C. for 1 hour. The suspension was filtered and the solid was washed with 1: 3 DMSO: DCM (106 mL, 2 V) and pure DCM (210 mL, 2 V). 3 times pulverized at 4 V). The solid was dried under vacuum at 60 ° C. for 24 hours to give lembatinib (I) (34.07 g, 79.81 mmol, crystallization yield = 79%, total yield = 67%). Obtained. A typical A% HPLC purity is 99.5% and the impurity content is reported in Table 1.

^{1 1} H-NMR (400MHz, DMSO-d6) δ (ppm): 0.43 (2H, m), 0.65 (2H, m), 2.57 (1H, m), 4.08 (3H, s) ), 6.46 (1H, d, J = 6.6Hz), 7.18 (1H, brs), 7.25 (1H, dd, J = 2.8Hz, J = 9.1Hz), 7.48 (1H, d, J = 2.8Hz), 7.52 (1H, s), 7.70 (1H, s), 7.83 (1H, s), 7.96 (1H, s), 8. 25 (1H, d, J = 9.1Hz), 8.63 (2H, m).

Example 4 Crystal form of mesylate salt of 4- (3-chloro-4- (cyclopropylaminocarbonyl) aminophenoxy) -7-methoxy-6-quinolincarboxamide lembatinib free base (6.81 g) obtained according to Example 3. , 15.9 mmol, 1 equivalent) in acetic acid (18.4 mL, 2.7 V) and diluted with acetic acid (2 mL, 0.3 V) methanesulfonic acid (1.0 mL, 15.9 mmol, 1 equivalent). Was added. The mixture was stirred at 60 ° C. for 30 minutes to dissolve completely. The solution was passed through a Whatman 0.2 μm filter and reheated at 60 ° C. Ethyl acetate (6.8 mL, 1 V) was added dropwise and the mixture was cooled to 40 ° C. The mixture was stirred at 40 ° C. for 16 hours and at room temperature for 1 hour. The suspension was filtered and the solid was washed with 3: 1 acetic acid: EtOAc (6.8 mL, 1 V). The wet solid (ACA-1 form, 18.25 g) was dried in vacuum at 60 ° C. for 72 hours and at 70 ° C. for an additional 24 hours to give the title compound the ACA-1-HT dry solid form (6.22 g, 11. 9 mmol, y = 75%). A typical A% HPLC purity was 99.8%.

^{1 1} H-NMR (DMSO-d ₆ ) δ (ppm): 0.43 (2H, m, H _9'A H _10'A ), 0.65 (2H, m, H _9'B , H _10'B) ), 2.40 (3H, s, CH 3 SO 3 H), 2.57 (1H, m, H 8 '), 4.08 (3H, s, OMe), 6.96 (1H, d, J = 6.6Hz, H ₃ ), 7.25 (1H, brass, NH _8' ), 7.35 (1H, dd, J = 2.8Hz, J = 9.1Hz, H _6' ), 7.62 (1H, d, J = 2.8Hz, H _2' ), 7.70 (1H, s, H ₈ ), 7.87 (1H, s, NH ₁₀ ), 7.94 (1H, s, NH ₁₀₎ ), 8.06 (1h, s, NH _4' ), 8.34 (1H, d, J = 9.1Hz, H _5' ), 8.71 (1H, s, H ₅ ), 8.97 ( 1H, d, J = 6.6Hz, H ₂ ).

Claims (4)

A method for producing lenvatinib of the formula (I).

(a) 1 equivalent of 4-chloro-7-methoxyquinoline-6-carboxamide (VI) and 2 equivalents of compound of formula (V) in the range of 45 ° C to 55 ° C in dimethyl sulfoxide in the presence of cesium carbonate. The step of reacting at temperature to obtain lenvatinib (I), and

(b) 1: 3 dimethyl sulfoxide: the step of crystallizing lenvatinib (I) in dichloromethane,
Manufacturing method including. The manufacturing method according to claim 1, wherein the step (a) is performed at 50 ° C. The production method according to claim 1 or 2, wherein the step (a) is carried out in the presence of 2 equivalents of cesium carbonate. Compound (V) is
In the presence of saturated sodium bicarbonate solution in 2-methyltetrahydrofuran, 4-amino-3-chlorophenol (II) is reacted with phenylchloroformate to contain the aqueous phase and the compound of formula (III). Obtain an organic phase,
-Separate the aqueous phase and add cyclopropylamine (IV) to the organic phase.

− Acid wash and crystallize in 4: 1 ethyl acetate: heptane,
The manufacturing method according to any one of claims 1 to 3 obtained thereby.